Infection by the human immunodeficiency virus (HIV) leads to AIDS, an incurable and inevitably fatal disease. A variety of biological agents are currently in use for the treatment of HIV-1 infections (Chaudry M N, and Shepp D H, Dermatol Clin. 15:2, 319-29 (1997); Beach J W, Clin Ther, 1998 January-February, 20:1, 2-25. HIV is a retrovirus and carries its genetic information as RNA. After infection, this viral genomic RNA must be converted into viral DNA. Multiple steps are involved in this crucial step of HIV replication, each of which is catalysed by the viral enzyme reverse transcriptase (RT) (Arnold, E. et al., Drug Des. Discov., 1996 April, 13:3-4, 29-47). RT has three enzymatic activities, RNA-dependent DNA polymerase activity (RDDP), ribonuclease H activity (RNase H), and DNA-dependent DNA polymerase activity (DDDP). With no mammalian counterpart, RT is an important target for antiviral development. Many such inhibitors have been discovered, including dideoxynucleosides (ddN) such as 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxy-3'-thiacytidine (3TC) and nonnucleoside inhibitors (NNI) such as nevirapine, quinoxalines, pyridinones and BHAP. Virtually all of these inhibitors are directed against the RDDP and/or DDDP activity of RT.
Once viral DNA synthesis is complete, the viral DNA is integrated into the infected host cell's DNA, in a reaction catalyzed by the viral enzyme integrase (IN). This proviral DNA encodes the genetic information to produce new HIV virions (virus particles), and is inaccessible to antiviral intervention in this state.
Cellular machinery is used to synthesize new HIV RNA and proteins from the genetic information in the proviral DNA. These viral components assemble at the cell plasma membrane, and the nascent virions are shed from the cell. Nascent HIV virions assemble in an "immature" form; viral maturation takes place during and after virion shedding. This maturation involves proteolytic processing of virion proteins, a process, which is carried out by the HIV protease. Immature HIV virions are noninfectious, thus the HIV protease has proven to be another important target for antiviral intervention. Inhibitors of HIV protease include saquinavir, indinavir and ritonavir.
The steps of HIV replication up to the formation of proviral DNA can be considered "pre-integrational" stages, and those involved in the formation of nascent virions after integration of proviral DNA can be considered as "post-integrational." Current chemotherapy of HIV-infected individuals utilizes combinations of RT inhibitors and HIV protease inhibitors. Clinical efficacy of these combinations is due in part to inhibition at both pre-integrational stages (RT) and post-integrational stages (protease) of HIV replication (McIntosh E M, et al., Acta Biochim Pol, 1996, 43:4, 583-92).
A number of antiviral agents exhibit low solubility and stability in physiological fluids. Often, chemotherapeutic agents are poorly transported across cell membranes. Further, many of these agents are binding with plasma proteins as well as other nonspecific interactions in the blood stream before they can reach the pharmacological target. Additionally, there is another serious problem associated with current anti-HIV chemotherapeutics. Although treatment with currently approved antivirals initially improves the quality of life and longevity of HIV-infected patients, prolonged therapy inevitably leads to drug-resistance (Kuritzkes D R, AIDS, Dec. 10, 1996 Suppl 5: S27-31; Richman D D, Adv Exp Med Biol, 1996, 394: 383-95). Resistance to RT inhibitors correlates with mutations in RT, and resistance to protease inhibitors correlates with mutations in the HIV protease. Clinical appearance of drug-resistant HIV imparts an unfavourable prognosis.